Specific cell surface receptors for transferrin, the iron transport protein, have been identified on both hemoglobin producing cells and non-hemoglobin producing proliferating cells. Recently, utilizing both a radioimmunoassay and transferrin binding studies, we have measured the transferrin receptor present on reticulocytes and nucleated cells in tissue culture. Receptor density on reticulocytes rapidly declines as the cells mature. However, on non-hemoglobin producing normal and leukemic cells, the density of both total cellular immunoreactive receptor molecules and transferrin binding sites are directly related to the state of cell proliferation. Further studies will relate the appearance of the receptor on normal, malignant, and proliferating hemoglobin producing cells to the relative state of cell growth and specific stage in the cell cycle. Other studies will measure the effect of inhibitors of both transferrin binding and iron uptake on cellular proliferation. Studies will be performed comparing the structure of the transferrin receptor on both normal and malignant cells, as well as certain Chinese hamster-human hybrid cell lines which synthesize human transferrin receptor. Cellular iron uptake, retention, and release, will be measured under different conditions. Further studies will determine ferritin content and differences in ferritin structure in different human cell types, as well as selected Chinese hamster-human hybrid cell lines which specifically synthesize human ferritin. These studies will be performed in concert with studies utilizing cells from patients with hemochromatosis, the genetic iron overload disease. The experiments proposed above will lead to a better understanding of iron metabolism in normal and pathologic conditions, including neoplasia, and hereditary hemochromatosis. These studies may also advance the knowledge of membrane receptor metabolism in general. Also, new information concerning mechanisms associated with cellular proliferation in normal and malignant cells may have future therapeutic implications for the treatment of humnan neoplasia.